1. Field of the Invention
The present invention relates generally to implantable devices, examples of which include stents and grafts. More particularly, the present invention is directed to an improved method of coating an implantable device with a therapeutic substance.
2. Description of the Related Art
Percutaneous transluminal coronary angioplasty (PTCA) is a procedure for treating heart disease. A catheter assembly having a balloon portion is introduced percutaneously into the cardiovascular system of a patient via the brachial or femoral artery. The catheter assembly is advanced through the coronary vasculature until the balloon portion is positioned across the occlusive lesion. Once in position across the lesion, the balloon is inflated to a predetermined size to radially press against the atherosclerotic plaque of the lesion to remodel the vessel wall. The balloon is then deflated to a smaller profile to allow the catheter to be withdrawn from the patient""s vasculature.
A problem associated with the above procedure includes formation of intimal flaps or torn arterial linings which can collapse and occlude the vessel after the balloon is deflated. Moreover, thrombosis and restenosis of the artery may develop over several months after the procedure, which may require another angioplasty procedure or a surgical by-pass operation. To reduce the partial or total occlusion of the artery by the collapse of arterial lining and to reduce the chance of the development of thrombosis and restenosis, a prosthesis, examples of which include stents and grafts, is implanted.
Stents are scaffoldings, usually cylindrical or tubular in shape, which function to physically hold open and, if desired, to expand the wall of the vessel. Typically stents are capable of being compressed, so that they may be inserted through small cavities via catheters, and then expanded to a larger diameter once they are at the desired location. Examples in patent literature disclosing stents which have been applied in PTCA procedures include stents illustrated in U.S. Pat. No. 4,733,665 issued to Palmaz, U.S. Pat. No. 4,800,882 issued to Gianturco, and U.S. Pat. No. 4,886,062 issued to Wiktor.
Synthetic vascular grafts are vessel-like configurations that may be positioned into the host blood vessel as a replacement for a diseased or occluded segment that has been removed. Alternatively, a graft may be sutured to the host vessel at each end so as to form a bypass conduit around a diseased or occluded segment of the host vessel.
Although stents and grafts are significant innovations in the treatment of occluded vessels, there remains a need for administering therapeutic substances to the treatment site. To provide an efficacious concentration to the treatment site, systemic administration of the therapeutic substance often produces adverse or toxic side effects for the patient. Local delivery is a highly suitable method of treatment, in that smaller levels of therapeutic substances, as compared to systemic dosages, are concentrated at a specific site. Local delivery produces fewer side effects and achieves more effective results.
One technique for the local delivery of therapeutic substances is through the use of medicated coatings on implantable devices. A common method for medicating a prosthesis involves the use of a polymeric carrier coated onto the surface of the prosthesis. A composition is formed by dissolving a therapeutic substance in a solution containing a polymer and a solvent. The composition is applied to the prosthesis using conventional techniques, such as spray-coating or dip-coating. The solvent is then removed, leaving on the prosthesis surface a coating of the polymer and the therapeutic substance impregnated in the polymer.
A shortcoming of the above-described method is the burst effect, in which an initial rapid release of therapeutic substance upon implantation of the prosthesis is followed by a slower, sustained release of therapeutic substance. Of the various factors which contribute to the burst effect, two factors stem from drying a solution-based coating. First, solution-based coating almost invariably results in an asymmetric distribution of therapeutic substance in the matrix. A higher concentration of therapeutic substance exists at the drying surface, or polymer-air interface, since the therapeutic substance concentrates where the solvent was at the end of the drying process. Additionally, a solvent-dried system may result in the therapeutic substance being in an amorphous phase. When the therapeutic substance is amorphous, as opposed to crystalline, the therapeutic substance exists as individual molecules in the matrix. These molecules may diffuse freely without first having to dissolve into the matrix as they would from a more crystalline phase and therefore contribute to the initial burst of therapeutic substance upon implantation of the prosthesis.
Another shortcoming of the above-described method for medicating a prosthesis is that the method does not facilitate processing every therapeutic substance with every polymer and solvent combination. Some therapeutic substances are very delicate and thus cannot tolerate processing in the presence of a solvent and/or a polymer for extended periods of time. This is especially true for peptide-type therapeutic substances, such as actinomycin D and others, having tertiary structure susceptible to transmutation from their native forms.
In accordance with on embodiment of the invention, a method of producing a composition which can be used for coating a medical device is provided. The method includes dissolving a therapeutic substance with a first fluid to form a solution; and combining a second fluid to the solution to form the composition, wherein the addition of the second fluid causes said therapeutic substance to precipitate. In one embodiment, the method additionally includes adding a polymeric material to the solution or the composition.
In accordance with another embodiment, a composition for coating a stent is provided, comprising a therapeutic substance, a first fluid and a second fluid, wherein the first fluid is a non-solvent for the therapeutic substance and wherein the second fluid is a solvent for the therapeutic substance. The first fluid can be, for example, deionized water, methanol, ethanol, freon and acetonitrile. The first fluid can be capable of dissolving about 30% or less of the total amount of therapeutic substance in the composition. The composition can additionally include a polymeric material
In yet another embodiment, a composition for coating an implantable medical device, such as a stent, is provided comprising a drug, a first fluid which is capable of dissolving a selected quantity of the drug added to the first fluid and a second fluid which allows for a colloidal formation of the drug in the composition. The first fluid can comprise about 50% to about 99% by weight of the total weight of the composition, the drug can comprise from about 0.5% to about 30% by weight of the total weight of the composition, and the second fluid can comprise from about 0.5% to about 20% by weight of the total weight of the composition. In one embodiment, the second fluid is not capable of dissolving more than 30% of the total weight of the drug added to the composition. The composition can additionally include a polymeric material. In this embodiment, the polymeric material can comprise from about 0.1% to about 30% by weight of the total weight of the composition, the first fluid can comprise from about 20% to about 89.9% by weight of the total weight of the composition, the drug can comprise from about 0.5% to about 30% by weight of the total weight of the composition, and the second fluid can comprise from about 0.5% to about 20% by weight of the total weight of the composition.